Background： The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma- 1 receptor agonist PRE-084 exhibits a cardioprotective effect in some stu...Background： The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma- 1 receptor agonist PRE-084 exhibits a cardioprotective effect in some studies, the benefits in cases of myocardial ischemia/reperfusion （I/R） are not clear. The aim of this study was to explore the mechanism of action and assess the effect of PRE-084 on myocardial I/R injury in rats. Methods： In this study, rats were assigned randomly to three groups with computer （n = 14 for each group）： a sham group, an I/R group, and a PRE-084 group. In the PRE-084 group, rats were administered PRE-084 I h before operation. In the myocardial I/R model, the left anterior descending branch of rats was ligated and opened half an hour later. Cardiac function was assessed, and the apoptosis index was evaluated. The mechanisms of the cardioprotective effects of PRE-084 were explored. Results： PRE-084 pretreatment preserved cardiac function and reduced myocardial apoptosis （F= 86.0, P 〈 0.01） with Western blotting analysis, showing significantly reduced expression of Bax （F = 75.7, P 〈 0.01） and cleaved-caspase 3 （F = 44.7, P 〈 0.01）, along with increased expression of the Bcl-2 protein （P 〈 0.01 ） and phosphorylated protein kinase B （p-Akt） （P 〈 0.01） and phosphorylated-endothelial nitric oxide synthase （p-eNOS; P 〈 0.01）. Conclusion： PRE-084 preserved cardiac function and reduced myocardial apoptosis through the activation of Akt and eNOS.展开更多
To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction ...To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor(α7-nAChR)and sigma-1 receptor(σ1-R)could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease.In this context,the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide(PHA)543613 as an α7-nAChR agonist and 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate(PRE)-084 as aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease.The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 postlesion.Although no effect was noticed in the amphetamine-induced rotation test,our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons(15-20%),assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra.Furthermore,this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion,i.e,the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum,and the CD11b and glial fibrillary acidic protein staining in the substantia nigra.Hence,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation.The study was approved by the Regional Ethics Committee(CEEA Val de Loire n°19)validated this protocol(Authorization N°00434.02)on May 15,2014.展开更多
文摘Background： The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma- 1 receptor agonist PRE-084 exhibits a cardioprotective effect in some studies, the benefits in cases of myocardial ischemia/reperfusion （I/R） are not clear. The aim of this study was to explore the mechanism of action and assess the effect of PRE-084 on myocardial I/R injury in rats. Methods： In this study, rats were assigned randomly to three groups with computer （n = 14 for each group）： a sham group, an I/R group, and a PRE-084 group. In the PRE-084 group, rats were administered PRE-084 I h before operation. In the myocardial I/R model, the left anterior descending branch of rats was ligated and opened half an hour later. Cardiac function was assessed, and the apoptosis index was evaluated. The mechanisms of the cardioprotective effects of PRE-084 were explored. Results： PRE-084 pretreatment preserved cardiac function and reduced myocardial apoptosis （F= 86.0, P 〈 0.01） with Western blotting analysis, showing significantly reduced expression of Bax （F = 75.7, P 〈 0.01） and cleaved-caspase 3 （F = 44.7, P 〈 0.01）, along with increased expression of the Bcl-2 protein （P 〈 0.01 ） and phosphorylated protein kinase B （p-Akt） （P 〈 0.01） and phosphorylated-endothelial nitric oxide synthase （p-eNOS; P 〈 0.01）. Conclusion： PRE-084 preserved cardiac function and reduced myocardial apoptosis through the activation of Akt and eNOS.
基金supported by Inserm(to SV,LFF,CT,JV,SB,SS,SC)by the Labex IRON(ANR-11-LABX-18-01:to all authors).
文摘To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s disease.It was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor(α7-nAChR)and sigma-1 receptor(σ1-R)could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s disease.In this context,the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide(PHA)543613 as an α7-nAChR agonist and 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate(PRE)-084 as aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s disease.The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 postlesion.Although no effect was noticed in the amphetamine-induced rotation test,our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons(15-20%),assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra.Furthermore,this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion,i.e,the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum,and the CD11b and glial fibrillary acidic protein staining in the substantia nigra.Hence,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation.The study was approved by the Regional Ethics Committee(CEEA Val de Loire n°19)validated this protocol(Authorization N°00434.02)on May 15,2014.
